Prostate-specific Membrane Antigen (PSMA), also known as glutamate carboxypeptidase II and N-acetylated alpha-linked acidic dipeptidase 1, is a dimeric type II transmembrane glycoprotein belonging to the M28 peptidase family encoded by the gene FOLH1 (folate hydrolase 1). The protein acts as a glutamate carboxypeptidase on different alternative substrates, including the nutrient folate and the neuropeptide N-acetyl-l-aspartyl-l-glutamate and is expressed in a number of tissues such as the prostate, and to a lesser extent, the small intestine, central and peripheral nervous system and kidney. The gene encoding PSMA is alternatively spliced to produce at least three variants. A mutation in this gene may be associated with impaired intestinal absorption of dietary folates, resulting in low blood folate levels and consequent hyperhomocysteinemia. Expression of this protein in the brain may be involved in a number of pathological conditions associated with glutamate excitotoxicity.
PSMA is a well-established, highly restricted prostate-cancer-related cell membrane antigen. In prostate cancer cells, PSMA is expressed 1000-fold higher than on normal prostate epithelium (Su et al., Cancer Res. 1995 44:1441-1443). Expression of PSMA increases with prostate cancer progression and is highest in metastatic disease, hormone refractory cases, and higher-grade lesions (Israeli et al., Cancer Res. 1994, 54:1807-1811; Wright et al., Urologic Oncology: Seminars and Original Investigations 1995 1:18-28; Wright et al., Urology 1996 48:326-332; Sweat et al., Urology 1998 52:637-640). Additionally, PSMA is abundantly expressed on the neovasculature of a variety of other solid tumors, including bladder, pancreas, melanoma, lung and kidney cancers, but not on normal neovasculature (Chang et al., Urology 2001 57:801-805; Divgi et al., Clin. Cancer Res. 1998 4:2729-3279).
PSMA has been shown to be an important target for immunological approaches such as vaccines or directed therapy with monoclonal antibodies. Unlike other prostate-restricted molecules that are secretory proteins (PSA, prostatic acid phosphatase), PSMA is an integral cell—surface membrane protein that is not secreted, which makes it an ideal target for antibody therapy. PROSTASCINT® (capromab pendetide) is an 111In-labelled anti-PSMA murine monoclonal antibody approved by the FDA for imaging and staging of newly diagnosed and recurrent prostate cancer patients (Hinkle et al., Cancer 1998, 83:739-747). However, capromab binds to an intracellular epitope of PSMA, requiring internalization or exposure of the internal domain of PSMA, therefore preferentially binding apoptotic or necrosing cells (Troyer et al., Urologic Oncology: Seminars and Original Investigations 1995 1:29-37; Troyer et al., Prostate 1997 30:232-242). As a result, capromab may not be of therapeutic benefit (Liu et al., Cancer Res. 1997 57:3629-3634).
Other monoclonal antibodies which target the external domain of PSMA have been developed (e.g., J591, J415, J533, and E99) (Liu et al., Cancer Res. 1997 57:3629-3634). Radiolabelled J591 is currently in clinical trials (Tagawa et al., Cancer 2010 116(S4):1075). However, evidence suggests that PSMA may act as a receptor mediating the internalization of a putative ligand. PSMA undergoes internalization constitutively, and PSMA-specific antibodies can induce and/or increase the rate of internalization, which then causes the antibodies to accumulate in the endosomes (Liu et al., Cancer Res. 1998 58:4055-4060). While PSMA-specific internalizing antibodies may aid in the development of therapeutics to target the delivery of toxins, drugs, or radioisotopes to the interior of prostate cancer cells (Tagawa et al., Cancer 2010 116(S4):1075), PSMA-specific antibodies utilizing native or engineered effector mechanisms (e.g., antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated phagocytosis (ADCP), or re-directed T-cell cytotoxicity (RTCC)) are problematic since the PSMA-specific antibody may be internalized before it is recognized by effector cells.